Pharmacologically active 4,8-dimethoxy-furo (3{40 ,2{40 -F)benzoxazol-2-yl acethydroxamic acid

ABSTRACT

A compound of the formula   IS PREPARED BY CONDENSING 4-AMINO-3-HYDROXY-2,5-DIMETHOXY BENZOFURAN WITH ETHYL IMINOMALONATE HYDROCHLORIDE TO FORM THE INTERMEDIATE 2-ETHOXYCARBONYLMETHYL-4,8-DIMETHOXY-FURO(3&#39;&#39;,2&#39;&#39;-F) BENZOXAZOLE AND THEN REACTING THE INTERMEDIATE WITH HYDROXYLAMINE HYDROCHLORIDE. The first-mentioned compound possesses vasodilatatory, antibronchoconstrictive, anticholinergic, antihistaminic, antiserotonic, antibradykinine, hypotensive, peripheral vasodilatatory and cardiac analeptic properties.

United States Patent [191 Fauran et al.

[ Nov. 25, 1975 [73] Assignee: Delalande S.A., Courbevoie, France [22] Filed: Feb. 14, 1974 [21] Appl. No.: 442,757

[30] Foreign Application Priority Data Feb. 19, 1973 France 73.05816 [52] US. Cl... 260/307 D; 260/346.2 R; 260/482 R;

- 424/272 [51] Int. Cl. C07D 498/14 [58] Field of Search 260/307 D [56] References Cited I FOREIGN PATENTS OR APPLICATIONS 1,087,779 10/1967 United Kingdom OTHER PUBLICATIONS Wagner et al., Synthetic Organic Chemistry," 1953,

Wiley and Sons, Inc., New York, p. 569.

Primary ExantinerRaymond V. Rush Attorney, Agent, or FirmWoodhams, Blanchard and Flynn [57] ABSTRACT A compound of the formula OCH OCH

is prepared by condensing 4-amino-3-hydroxy-2,5-

-dimethoxy benzofuran with ethyl iminomalonate hydrochloride to form the intermediate 2- ethoxycarbonyImethyl-4,8-dimethoxy-furo(3,2-f) benzoxazole and then reacting the intermediate with hydroxylamine hydrochloride. The first-mentioned compound possesses vasodilatatory, antibronchoconstrictive, anticholinergic, antihistaminic, antiserotonic, antibradykinine, hypotensive, peripheral vasodilatatory and cardiac analeptic properties.

1 Claim, No Drawings 1 2 PI-IARMACOLOGICALLY ACTIVE acid gas. The suspension is warmed to 90-95C for 4,8-DIMETIIOXY-FURO hour, diluted with 800 ml of water and the temperature (3',2'-F)BENZOXAZOL -3-YL ACETIIYDROXAMIC of the reaction mixture is maintained at 50C for 1 ACID hour. The solution obtained is then cooled to O-5C.

5 filtered and the compound obtained is recrystallised The present invention relates to 4,8-dimethoxy-furo from methanol. (3',2'-f) benzoxazol-Z-yl acethydroxamic acid, its pro- Melting p in 160C; yi l mpi ical f cess of preparation and its therapeutic application. mula 12 l-3 5- The novel acid according to the invention corre- 1O sponds to the following formula:

Elementary analysis:

2nd stage: 5-amino-6-hydroxy-4,7-dimethoxy benzo- O 3 1 2O furan. (Code No. 70344) 0.88 mol of 5-acetamido-6rhydroxy-4,7-dimethox- The process according to the invention consists of: ybenzofuran in suspension in 1.751 of 2N hydrochloric in a first stage, condensing 4-amino-3-hydroxy-2,5- ethanol is heated under reflux for 24 hours. dimethoxy benzofuran of formula 11, with ethyl The amide is rapidly solubilised and a clear brown soiminomalonate hydrochloride of formula III; lution is obtained. After 24 hours the solution is diluted H01, an

to form 2-ethoxycarbonylmethyl-4,8dimethoxy-furo with ll of water, the ethanol is removed, and any amide (3',2'-f) benzoxazole of formula IV: which has not reacted is removed by extraction with ethyl acetate.

The solution is neutralised to pH 4 with 2N soda, added dropwise with good agitation. 5-amino-6- hydr0xy-4,7-dimethoxybenzofuran is obtained which may be recrystallised from water, but which is utilised as such in the following synthesis.

Melting point 131C; yield 80%; empirical formula c ,r-l,,No.,.

and in a second stage, reacting in sodium methanolate, Elementary analysis: hydroxylamine hydrochloride of formula: NH OH, c H N HCl with the derivative of formula IV. Calculated?! 57.41 530 6.70 The compound of formula II is obtained by heating Found% 57.66 5.33 6.87 under reflux for 24 hours in 2N hydrochloric ethanol, 5-acetamido-6-hydroxy-4,7-dimethoxybenzofuran, which results from hydroxylation of 4,8-dimethoxy-2- methyl'furo (3I2I'f) benzoxazole itself prepared by zoxazo1-2-yl acethydroxamic acid (Code No. 71315) subjecting khellinone oxime to the Beckmann rear- 1st Stage. 2 ethoxycarbony]methy] 48 dimethoxy rangemfimfuro (3',2-f) benzoxazole. (Code No: 70 417) The following preparation is given by way-of exam- A mixture of 0025mm of 4 aminO 3 hydroXy 2,5

b. Preparation of 4,8-dimethoxy-furo(3',2'-f) bento illustrate the invention dimethoxybenzofuran, 0.025 mol of ethyl iminomalon- EXAMPLE ate hydrochloride and 12ml of anhydrous ethanol is maintained under reflux for 2 hours. The precipitate of 4is'dlmethoxy'furo j bejnzoxazol'z'yl NH Cl formed is separated and the filtrate is evapoacethydroxamlc 861d rated to dryness. The residue is taken up in chloroform a. Preparation of 5-amino-6-hydroxy-4,7-dimethoxy and washed with water. The product obtained by evapbenzofuran 1st. stage: 5-acetamido-6-hydroxy-4,7- oration is recrystallised from ethanol in the presence of dimethoxy benzofuran (Code No. 70244) animal-black.

0.2 mol of khellinone oxime is placed in suspension Melting point=58C; yield=58%;empirical formula in 250 ml of acetic acid saturated with hydrochloric =C, H NO Elementary analysis:

C H N Calculated? 59.01 4.95 4.59 Found?! 5911 4.85 4.70

2nd stage: 4,8-dimeth'oxy-furo (3',2-f) benzoxazol- 2-yl acethydroxamic acid.

0.23 mol of hydroxylamine hydrochloride in solution in 220ml of anhydrous methanol is added to a solution of sodium methanolate prepared from 0.49 atom of sodium and 100ml of anhydrous methanol. The precipitate of NaCl formed is filtered off and 0.23 mol of 2, ethoxycarbonylmethyl-4,8-dimethoxy-furo (3,2'-f) benzoxazole is added to the filtrate. The mixture is maintained under reflux for i k hours. The product obtained by evaporation is solubilised in 300ml of water, and is then acidified with concentrated HCl. The precipitate formed is filtered and recrystallised in the presence of animalblack from a ethanol-dimethylformamide mixture, in ratio of 9:1 by volume.

Melting point 213C; yield 51%; empirical formula C I-I, N O

Elementary analysis:

The compound of formula (I) has been tested on animals in the laboratory and has been shown to possess vasodilatatory, antibronchoconstrictive and anticholinergic antihistaminic, antiserotonic, antibradykinine, hypotensive, peripheral vasodilatatory and cardiac analeptic properties.

1. Vasodilatatory properties The compound of formula (I) is capable of augmenting the flow of the coronary vessels of the isolated heart of a guinea-pig, when said compound is added in the perfusion liquid of said organ.

Thus, in a dose of 2.5p.g/m1 in the perfusion liquid, it augments by 60% the flow of the isolated heart.

2. Antibronchoconstrictive, anticholinergic, antibradykinine, antihistaminic and antiserotonic properties Injected by intraveinous means, the compound of formula (I) is capable of opposing the bronchoconstriction provoked in the guinea-pig by the intraveinous injection of acetylcholine, bradykinine, histamine or serotonine. The antibronchoconstrictive effect is evaluated by the Konzett method.

There is listed in the following Table the results obtained by administration of the compounds of formula TABLE Broncho- Dose administered Percentage constrictural of compound of reduction of Agent formula I bronchoconstriction (mg/kg/i.v.) (71) histamine 0.9 50 serotonine l 50 acetylecholine 2.5 50 bradykinine 0.5 50

In addition, the compound of formula (I), in a does of 50ug/ml permits a relaxation of 100% of the isolated tracheal chain, contracted by histamine.

3. Hypotensive properties Administered by intraveinous means to an anaesthetised cat, the compound of formula (I) causes a lowering of the arterial pressure.

Thus, administered in a dose of 8mg/kg/Lv. the com H pound of formula (I) permits a reductionof 50% in the arterial pressure of an anaesthetised cat, which lasts for 20 minutes.

4. Peripheral vasodilatatory properties The compound of formula (I), administered by intraarterial means inra dose which will not affect the arte- 7 rial pressure, provokes an augmentation of flow ofthe femoral artery, the level of which is effectuated by the 1 injection, in an anaesthetised dog with femoral carotid anastomosis, the measure being effectuated by a rotameter situated at the level of the derivation.

In an lOOug/kg/La. of the compound of formula (1), produces, for two minutes, an augmentation of of the femoral flow.

5. Cardiac analeptic properties The compound of formula (I) is capable of augmenting the force of contractions of the isolated left auricle of an electrically stimulated guinea-pig.

Thus, in a concentration of IOug/ml in the conserv ing liquid, it permits an augmentation of the. force of contractions of left auricle of a electrically stimulated guinea-pig.

In addition, administered to a dog by .intraveinous 5 means, the compound of formula (I) augments the am: plitude of the frequency of cardiac contractions.

Thus, the administration of ZOmg/kg/Lv. of the com-.

pound of formula (I), produce, for 35 minutes, an augmentation of 55% of the cardiac frequency and, for 15 minutes, an augmentation of 55% of the cardiac ampli'- tude.

Finally, as no mortality has been observed following the administration of 2g/kg/p.o. of the compound of formula (I), the difference between the lethal dose and the pharmacologically active doses is sufficiently great 1 to permit the compound of the formula (I) be utilised active ingredient (1 to 4 times a day) and by rectal means in the form of suppositories containing25 to 200mg of active ingredient (I or 2 times a'day);

Accordingly, the presentinvention also provides a, therapeutic composition comprising the compound of the formula (I) togetherwith a therapeutically-acceptable carrier.

What we claim is:

1. 4,8-dimethoxy-furo (3',2'-f)benzoxazo1-2-yl ace thydroxamic acid having the formula:

0 CH CO Nl-lOl-I indicative manner, the administration of 

1. 4,8-DIMETHOXY-FURO (3'',2''-F)BENZOXAZOL-2-YL ACETHYDROXAMIC ACID HAVING THE FORMULA: 